RESUMO
All areas of the modern society are affected by fluorine chemistry. In particular, fluorine plays an important role in medical, pharmaceutical and agrochemical sciences. Amongst various fluoro-organic compounds, trifluoromethyl (CF3) group is valuable in applications such as pharmaceuticals, agrochemicals and industrial chemicals. In the present study, following the strict OECD modelling principles, a quantitative structure-toxicity relationship (QSTR) modelling for the rat acute oral toxicity of trifluoromethyl compounds (TFMs) was established by genetic algorithm-multiple linear regression (GA-MLR) approach. All developed models were evaluated by various state-of-the-art validation metrics and the OECD principles. The best QSTR model included nine easily interpretable 2D molecular descriptors with clear physical and chemical significance. The mechanistic interpretation showed that the atom-type electro-topological state indices, molecular connectivity, ionization potential, lipophilicity and some autocorrelation coefficients are the main factors contributing to the acute oral toxicity of TFMs against rats. To validate that the selected 2D descriptors can effectively characterize the toxicity, we performed the chemical read-across analysis. We also compared the best QSTR model with public OPERA tool to demonstrate the reliability of the predictions. To further improve the prediction range of the QSTR model, we performed the consensus modelling. Finally, the optimum QSTR model was utilized to predict a true external set containing many untested/unknown TFMs for the first time. Overall, the developed model contributes to a more comprehensive safety assessment approach for novel CF3-containing pharmaceuticals or chemicals, reducing unnecessary chemical synthesis whilst saving the development cost of new drugs.
Assuntos
Relação Quantitativa Estrutura-Atividade , Testes de Toxicidade Aguda , Animais , Ratos , Administração Oral , Testes de Toxicidade Aguda/métodos , Algoritmos , Hidrocarbonetos Fluorados/toxicidade , Modelos LinearesRESUMO
HFC-134 is the main impurity of HFA-134a. In order to verify the rationality of HFC-134 limits in HFA-134a and ensure the safety of HFA-134a as propellant in pharmaceutical metered-dose inhalers, acute inhalation toxicity, seven-day repeat dose inhalation irritation study, 21-day repeat dose inhalation toxicity study and reverse mutation assay of HFC-134 were tested to evaluate its inhalation safety. In acute inhalation studies, Sprague-Dawley rats were exposed nose-only to HFC-134 at levels of 100 000, 200 000, 400 000, 600 000, and 800 000 ppm for 4 h. Based on the mortality incidence, the calculated four-hour LC50 value for HFC-134 is 532 069 ppm for males and 502 058 ppm for females and acute inhalation toxicity is manifested as the lung lobes turn dark red. Exposures to 836 ± 67 ppm for 4 hours/day 7 days/week continuously did not induce local irritation of the respiratory system in Sprague-Dawley rats. Sprague-Dawley rats were exposed nose-only to HFC-134 at levels of 0 (control), 203 929 ppm and 394 871 ppm 2 h/day for 21 consecutive days, no significant treatment-related adverse effects was noted. Results from Ames studies demonstrated that HFC-134 was not mutagenic. Although HFC-134 has a very low acute inhalation toxicity, considering that its acute inhalation toxicity is higher than that of HFA-134a, and due to the high frequency of use of MDI by asthma patients, acceptance criteria of HFC-134 as the impurity in aerosol propellant HFA-134a should be lower than 8-h TWA WEEL value of 1000 ppm to ensure the safety of the MDI.
Assuntos
Propelentes de Aerossol , Mutagênicos , Masculino , Ratos , Feminino , Animais , Propelentes de Aerossol/toxicidade , Ratos Sprague-Dawley , Hidrocarbonetos Fluorados/toxicidade , Administração por Inalação , Sistema RespiratórioRESUMO
As alternatives to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide dimer acid (HFPO-DA) and hexafluoropropylene oxide trimer acid (HFPO-TA) have raised concerns of their potential health risks. Human bone marrow mesenchymal stem cell was employed as an in vitro model to investigate the molecular targets and the adverse effects of HFPOs in stem cells in concentrations range starting at human relevant levels. Unsupervised transcriptomic analysis identified 1794 and 1429 DEGs affected by HFPO-TA and HFPO-DA, respectively. Cell cycle-associated biological processes were commonly altered by both chemicals. 18 and 35 KEGG pathways were enriched in HFPO-TA and HFPO-DA treatment group, respectively, among which multiple pathways were related to cancer and pluripotency. Few genes in PPAR signalling pathway were disturbed by HFPOs suggesting the involvement of PPAR-independent toxic mechanism. HFPO-TA promoted cell proliferation with significance at 1 µM mRNA levels of CDK and MYC were down-regulated by HFPOs, suggesting the negative feedback regulation to the abnormal cell proliferation. Decreased expression of CD44 protein, and ENG and THY1 mRNA levels demonstrated HFPOs-caused changes of hBMSCs phenotype. The osteogenic differentiation was also inhibited by HFPOs with reduced formation of calcium deposition. Furthermore, gene and protein expression of core pluripotency regulators NANOG was enhanced by HFPO-TA. The present study provides human relevant mechanistic evidence for health risk assessment of HFPOs, prioritizing comprehensive carcinogenicity assessment of this type of PFOA alternatives.
Assuntos
Fluorocarbonos , Hidrocarbonetos Fluorados , Células-Tronco Mesenquimais , Propionatos , Proliferação de Células , Fluorocarbonos/toxicidade , Humanos , Hidrocarbonetos Fluorados/toxicidade , Osteogênese , Propionatos/toxicidade , TranscriptomaRESUMO
Human exposure to per- and polyfluoroalkyl substances (PFAS) is ubiquitous, with mixtures of PFAS detected in drinking water, food, household dust, and other exposure sources. Animal toxicity studies and human epidemiology indicate that PFAS may act through shared mechanisms including activation of peroxisome proliferator activated receptor α (PPARα). However, the effect of PFAS mixtures on human relevant molecular initiating events remains an important data gap in the PFAS literature. Here, we tested the ability of modeling approaches to predict the effect of diverse PPARα ligands on receptor activity using Cos7 cells transiently transfected with a full length human PPARα (hPPARα) expression construct and a peroxisome proliferator response element-driven luciferase reporter. Cells were treated for 24 h with two full hPPARα agonists (pemafibrate and GW7647), a full and a partial hPPARα agonist (pemafibrate and mono(2-ethylhexyl) phthalate), or a full hPPARα agonist and a competitive antagonist (pemafibrate and GW6471). Receptor activity was modeled with three additive approaches: effect summation, relative potency factors (RPF), and generalized concentration addition (GCA). While RPF and GCA accurately predicted activity for mixtures of full hPPARα agonists, only GCA predicted activity for full and partial hPPARα agonists and a full agonist and antagonist. We then generated concentration response curves for seven PFAS, which were well-fit with three-parameter Hill functions. The four perfluorinated carboxylic acids (PFCA) tended to act as full hPPARα agonists while the three perfluorinated sulfonic acids (PFSA) tended to act as partial agonists that varied in efficacy between 28-67 % of the full agonist, positive control level. GCA and RPF performed equally well at predicting the effects of mixtures with three PFCAs, but only GCA predicted experimental activity with mixtures of PFSAs and a mixture of PFCAs and PFSAs at ratios found in the general population. We conclude that of the three approaches, GCA most accurately models the effect of PFAS mixtures on hPPARα activity in vitro. Understanding the differences in efficacy with which PFAS activate hPPARα is essential for accurately predicting the effects of PFAS mixtures. As PFAS can activate multiple nuclear receptors, future analyses should examine mixtures effects in intact cells where multiple molecular initiating events contribute to proximate effects and functional changes.
Assuntos
Ácidos Carboxílicos/toxicidade , Hidrocarbonetos Fluorados/toxicidade , Modelos Moleculares , PPAR alfa/agonistas , PPAR alfa/antagonistas & inibidores , Ácidos Sulfônicos/toxicidade , Animais , Células COS , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Agonismo Parcial de Drogas , Estrutura Molecular , PPAR alfa/genética , PPAR alfa/metabolismo , Transdução de Sinais , Relação Estrutura-AtividadeRESUMO
In two field experiments, performed in 2020 and 2021, potato Nicola plants were sprayed once with three (Exp. 1) or two (Exp. 2) doses of Zorvec Vinabel (oxathiapiprolin+ zoxamide = ZZ), Zorvec Encantia (oxathiapiprolin+ famoxadone = ZF), Zorvec Endavia (oxathiapiprolin+ benthiavalicarb = ZE), Infinito (= INF) or Mefenoxam (= MFX) and thereafter inoculated with genotype 23A1 or 36A2 of Phytophthora infestans. Disease development was recorded at periodic intervals for a month. In both experiments, Zorvec mixtures were significantly more effective in suppressing the disease than INF or MFX. They delayed the onset of the disease and its progress, regardless the genotype used for inoculation. Among the three Zorvec mixtures, ZZ was least effective and ZE most effective. Sensitivity monitoring assays revealed zero mutants of P. infestans resistant to oxathiapiprolin. The data confirmed good efficacy of Zorvec mixtures, especially ZE, in field-grown potato crops as evident by the very effective control of late blight for one month.
Assuntos
Fungicidas Industriais/toxicidade , Hidrocarbonetos Fluorados/toxicidade , Phytophthora infestans/efeitos dos fármacos , Phytophthora infestans/genética , Pirazóis/toxicidade , Área Sob a Curva , Resistência à Doença , Fazendas , Genótipo , Doenças das Plantas/microbiologia , Solanum tuberosum/microbiologia , Tempo (Meteorologia)RESUMO
HFC-43-10mee is a volatile liquid at room temperature and used as a cleaning agent, aerosol, etc. HFC-43-10mee has low acute inhalation toxicity; 4-hour LC50 in rats of approximately 11,000 ppm. The compound was not a skin or eye irritant and was not a skin sensitizer. A cardiac sensitization response was not observed at 5000 ppm. Inhalation exposure resulted in neurotoxicity consisting of tremors, convulsions, jerking, ataxia, abnormal gait, etc. at exposure concentrations of 2000 ppm and above. Within approximately 30 min of exposure the clinical signs appeared and resolved within 1-2 h during exposure; the rats appeared to adapt such that these clinical signs were no longer observed. The neurotoxicity observed was considered an acute response to HFC-43-10mee. In a 90-day study, rats exposed to 2000 ppm resulted in sporadic clinical signs of neurotoxicity. At 3500 ppm, the clinical signs were evident on most exposure days although as the study progressed the apparent incidence declined likely reflecting adaptation. The NOAEL was 500 ppm. Based on the occurrence of the clinical signs in this and other studies, an acute threshold for neurotoxicity was evident at approximately 2000 ppm and above. No developmental or reproductive toxicity were evident at 2000 ppm, although clinical signs of neurotoxicity occurred in maternal or parental rats at 2000 ppm. No effects on offspring were observed. HFC-43-10mee was not genotoxic in vitro or in vivo. Based on the data, the 8-h TWA WEEL value is 225 ppm (2320 mg/m3). The 15-min STEL is 700 ppm (7217 mg/m3).
Assuntos
Hidrocarbonetos Fluorados/toxicidade , Animais , Feminino , Humanos , Hidrocarbonetos Fluorados/efeitos adversos , Hidrocarbonetos Fluorados/química , Exposição por Inalação/efeitos adversos , Masculino , Nível de Efeito Adverso não Observado , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/normas , Ratos , Reprodução/efeitos dos fármacosRESUMO
Per- and polyfluorinated alkyl substances (PFAS) are ubiquitous, persistent, and toxic chemicals that pose public health risks. Recent carcinogenicity concerns have arisen based on epidemiological studies, animal tumor findings, and mechanistic data. Thousands of PFAS exist; however, current understanding of their toxicity is informed by studies of a select few, namely, perfluorooctanoic acid and perfluorooctanesulfonic acid. Hence, the computational, high-throughput screening tool, the US EPA CompTox Chemical Dashboard's ToxCast, was utilized to explore the carcinogenicity potential of PFAS. Twenty-three major PFAS that had sufficient in vitro ToxCast data and covered a range of structural subclasses were analyzed with the visual analytics software ToxPi, yielding a qualitative and quantitative assessment of PFAS activity in realms closely linked with carcinogenicity. A comprehensive literature search was also conducted to check the consistency of analyses with other mechanistic data streams. The PFAS were found to induce a vast range of biological perturbations, in line with several of the International Agency for Research on Cancer-defined key carcinogen characteristics. Patterns observed varied by length of fluorine-bonded chains and/or functional group within and between each key characteristic, suggesting some structure-based variability in activity. In general, the major conclusions drawn from the analysis, that is, the most notable activities being modulation of receptor-mediated effects and induction of oxidative stress, were supported by literature findings. The study helps enhance understanding of the mechanistic pathways that underlie the potential carcinogenicity of various PFAS and hence could assist in hazard identification and risk assessment for this emerging and relevant class of environmental toxicants.
Assuntos
Poluentes Ambientais/toxicidade , Ensaios de Triagem em Larga Escala/métodos , Hidrocarbonetos Fluorados/toxicidade , Animais , Testes de Carcinogenicidade , Bases de Dados de Compostos Químicos , Hidrocarbonetos Fluorados/química , Estrutura MolecularRESUMO
Fluorinated hydrocarbons, which can thermally degrade into toxic hydrofluoric acid, are widely used as, for example, cooling agents in refrigerators and air conditioning systems and as medical aerosol propellants. Hydrofluoric acid is a known causative agent of irritant-induced asthma. We report on two patients with asthma initiation shortly after exposure to fluorinated hydrocarbon-based cooling agents while welding or smoking cigarettes in a confined space. Both cases developed respiratory symptoms and headache and later demonstrated nonspecific bronchial hyperresponsiveness. In follow-up, asthma was persistent and responded poorly to asthma medication. Exposure to the fluorinated hydrocarbons themselves is unlikely to have caused asthma due to their low toxicity. Instead, exposure to small amounts of hydrofluoric acid via the thermal degradation of the fluorinated hydrocarbons was considered the most likely cause of asthma onset. This is supported by the typical clinical picture of irritant-induced asthma and acute symptoms resembling hydrofluoric acid poisoning. When fluorinated hydrocarbons are used in the presence of combustion, thermal degradation may lead to the formation of hydrofluoric acid. In confined spaces, this exposure may induce asthma via irritation. Welding, smoking, and other sources of combustion in confined spaces may be a risk in workplaces and other places in which fluorinated hydrocarbons are used.
Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Asma Ocupacional/induzido quimicamente , Hidrocarbonetos Fluorados/toxicidade , Exposição por Inalação/efeitos adversos , Exposição Ocupacional/efeitos adversos , Adulto , Hiper-Reatividade Brônquica/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/induzido quimicamente , Fumar/efeitos adversos , Combustão Espontânea , SoldagemRESUMO
During the last decades, the potential harmfulness derived from the exposure to environmental pollutants has been largely demonstrated, with associated damages ranging from geno- and cyto-toxicity to tissue malfunction and alterations in organism physiology. Autophagy is an evolutionarily-conserved cellular mechanism essential for cellular homeostasis, which contributes to protect cells from a wide variety of intracellular and extracellular stressors. Due to its pivotal importance, its correct functioning is directly linked to cell, tissue and organismal fitness. Environmental pollutants, particularly industrial compounds, are able to impact autophagic flux, either by increasing it as a protective response, by blocking it, or by switching its protective role toward a pro-cell death mechanism. Thus, the understanding of the effects of chemicals exposure on autophagy has become highly relevant, offering new potential approaches for risk assessment, protection and preventive measures to counteract the detrimental effects of environmental pollutants on human health.
Assuntos
Proteínas Relacionadas à Autofagia/fisiologia , Autofagia/fisiologia , Poluentes Ambientais/toxicidade , Animais , Apoptose/fisiologia , Morte Celular Autofágica/fisiologia , Autofagossomos/fisiologia , Autofagia/efeitos dos fármacos , Estresse do Retículo Endoplasmático , Exposição Ambiental , Poluentes Ambientais/farmacocinética , Poluentes Ambientais/farmacologia , Retardadores de Chama/toxicidade , Humanos , Hidrocarbonetos Fluorados/toxicidade , Lisossomos/fisiologia , Mitocôndrias/efeitos dos fármacos , Mitofagia/fisiologia , Modelos Animais , Fenóis/toxicidade , Ácidos Ftálicos/toxicidade , Xenobióticos/toxicidadeRESUMO
1,1,2,2-tetrafluoro-2-[1,1,1,2,3,3-hexafluoro-3-(1,1,2,2-tetrafluoroethoxy)propan-2-yl]oxyethane-1-sulfonic acid (PFESA-BP2) was first detected in 2012 in the Cape Fear River downstream of an industrial manufacturing facility. It was later detected in the finished drinking water of municipalities using the Cape Fear River for their water supply. No toxicology data exist for this contaminant despite known human exposure. To address this data gap, mice were dosed with PFESA-BP2 at 0, 0.04, 0.4, 3, and 6â¯mg/kg-day for 7 days by oral gavage. As an investigative study, the final dose groups evolved from an original dose of 3â¯mg/kg which produced liver enlargement and elevated liver enzymes. The dose range was extended to explore a no effect level. PFESA-BP2 was detected in the sera and liver of all treated mice. Treatment with PFESA-BP2 significantly increased the size of the liver for all mice at 3 and 6â¯mg/kg-day. At the 6â¯mg/kg-day dose, the liver more than doubled in size compared to the control group. Male mice treated with 3 and 6â¯mg/kg-day and females treated with 6â¯mg/kg-day demonstrated significantly elevated serum markers of liver injury including alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH), and liver/body weight percent. The percent of PFESA-BP2 in serum relative to the amount administered was similar in male and female mice, ranged from 9 to 13 %, and was not related to dose. The percent accumulation in the liver of the mice varied by sex (higher in males), ranged from 30 to 65 %, and correlated positively with increasing dose level.
Assuntos
Hidrocarbonetos Fluorados/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Relação Dose-Resposta a Droga , Feminino , Hidrocarbonetos Fluorados/sangue , Hidrocarbonetos Fluorados/farmacologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Tamanho do Órgão/efeitos dos fármacos , Poluentes Químicos da Água/sangue , Poluentes Químicos da Água/farmacocinéticaRESUMO
Chlordane is a worldwide banned organochlorine insecticide because of its hazard to animal and human health. It is also a persistent organic pollutant, which can affect either the soil or the aquatic life. The same applies to other chlorinated cyclodiene insecticides, such as dieldrin and aldrin. In turn, organofluorine compounds have a widespread use in agriculture. Therefore, density functional calculations and docking studies showed that the bioisosteric replacement of chlorines in the above-mentioned compounds by fluorines improves some physicochemical parameters used to estimate the toxicity and environmental risk of these compounds, as well as the ligand-enzyme (GABAA receptor-chloride channel complex) interactions related to their insecticidal activity. This work is an effort to provide an improved new class of organofluorine pesticides.
Assuntos
Hidrocarbonetos Clorados/química , Hidrocarbonetos Fluorados/química , Modelos Teóricos , Praguicidas/química , Receptores de GABA-A/química , Animais , Fenômenos Químicos , Halogenação , Humanos , Hidrocarbonetos Clorados/farmacologia , Hidrocarbonetos Clorados/toxicidade , Hidrocarbonetos Fluorados/farmacologia , Hidrocarbonetos Fluorados/toxicidade , Simulação de Acoplamento Molecular , Praguicidas/farmacologia , Praguicidas/toxicidadeRESUMO
GenX is an alternative to environmentally persistent long-chain perfluoroalkyl and polyfluoroalkyl substances. Mice exposed to GenX exhibit liver hypertrophy, elevated peroxisomal enzyme activity, and other apical endpoints consistent with peroxisome proliferators. To investigate the potential role of peroxisome proliferator-activated receptor alpha (PPARα) activation in mice, and other molecular signals potentially related to observed liver changes, RNA sequencing was conducted on paraffin-embedded liver sections from a 90-day subchronic toxicity study of GenX conducted in mice. Differentially expressed genes were identified for each treatment group, and gene set enrichment analysis was conducted using gene sets that represent biological processes and known canonical pathways. Peroxisome signaling and fatty acid metabolism were among the most significantly enriched gene sets in both sexes at 0.5 and 5 mg/kg GenX; no pathways were enriched at 0.1 mg/kg. Gene sets specific to the PPARα subtype were significantly enriched. These findings were phenotypically anchored to histopathological changes in the same tissue blocks: hypertrophy, mitoses, and apoptosis. In vitro PPARα transactivation assays indicated that GenX activates mouse PPARα. These results indicate that the liver changes observed in GenX-treated mice occur via a mode of action (MOA) involving PPARα, an important finding for human health risk assessment as this MOA has limited relevance to humans.
Assuntos
Hidrocarbonetos Fluorados/toxicidade , Fígado/efeitos dos fármacos , PPAR alfa/efeitos dos fármacos , Propionatos/toxicidade , Animais , Feminino , Humanos , Masculino , Camundongos , Medição de Risco , Transcriptoma/efeitos dos fármacosRESUMO
To accurately predict the environmental fate of per- and polyfluoroalkyl substances (PFAS), high-quality physicochemical property data are required. Because such data are often not available from experiments, assessment of the accuracy of existing property estimation models is essential. The quality of predicted physicochemical property data for a set of 25 PFAS was examined using COSMOtherm, EPI Suite, the estimation models accessible through the US Environmental Protection Agency's CompTox Chemicals Dashboard, and Linear Solvation Energy Relationships (LSERs) available through the UFZ-LSER Database. The results showed that COSMOtherm made the most accurate acid dissociation constant and air-water partition ratio estimates compared with literature data. The OPEn structure-activity/property Relationship App (OPERA; developed through the CompTox Chemicals Dashboard) estimates of vapor pressure and dry octanol-air partition ratios were the most accurate compared with other models of interest. Wet octanol-water partition ratios were comparably predicted by OPERA and EPI Suite, and the organic carbon soil coefficient and solubility were well predicted by OPERA and COSMOtherm. Acid dissociation of the perfluoroalkyl acids has a significant impact on their physicochemical properties, and corrections for ionization were included where applicable. Environ Toxicol Chem 2020;39:775-786. © 2020 SETAC.
Assuntos
Alcanos/química , Monitoramento Ambiental/métodos , Poluentes Ambientais/química , Hidrocarbonetos Fluorados/química , Modelos Químicos , Alcanos/análise , Alcanos/toxicidade , Poluentes Ambientais/análise , Poluentes Ambientais/toxicidade , Hidrocarbonetos Fluorados/análise , Hidrocarbonetos Fluorados/toxicidade , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Solubilidade , Termodinâmica , Estados Unidos , United States Environmental Protection AgencyRESUMO
BACKGROUND: Perfluorooctanoic acid (PFOA) is a poly- and perfluoroalkyl substance (PFAS) associated with adverse pregnancy outcomes in mice and humans, but little is known regarding one of its replacements, hexafluoropropylene oxide dimer acid (HFPO-DA, referred to here as GenX), both of which have been reported as contaminants in drinking water. OBJECTIVES: We compared the toxicity of PFOA and GenX in pregnant mice and their developing embryo-placenta units, with a specific focus on the placenta as a hypothesized target. METHODS: Pregnant CD-1 mice were exposed daily to PFOA (0, 1, or 5mg/kg) or GenX (0, 2, or 10mg/kg) via oral gavage from embryonic day (E) 1.5 to 11.5 or 17.5 to evaluate exposure effects on the dam and embryo-placenta unit. Gestational weight gain (GWG), maternal clinical chemistry, maternal liver histopathology, placental histopathology, embryo weight, placental weight, internal chemical dosimetry, and placental thyroid hormone levels were determined. RESULTS: Exposure to GenX or PFOA resulted in increased GWG, with increase in weight most prominent and of shortest latency with 10mg/kg/d GenX exposure. Embryo weight was significantly lower after exposure to 5mg/kg/d PFOA (9.4% decrease relative to controls). Effect sizes were similar for higher doses (5mg/kg/d PFOA and 10mg/kg/d GenX) and lower doses (1mg/kg/d PFOA and 2mg/kg/d GenX), including higher maternal liver weights, changes in liver histopathology, higher placental weights and embryo-placenta weight ratios, and greater incidence of placental abnormalities relative to controls. Histopathological features in placentas suggested that PFOA and GenX may exhibit divergent mechanisms of toxicity in the embryo-placenta unit, whereas PFOA- and GenX-exposed livers shared a similar constellation of adverse pathological features. CONCLUSIONS: Gestational exposure to GenX recapitulated many documented effects of PFOA in CD-1 mice, regardless of its much shorter reported half-life; however, adverse effects toward the placenta appear to have compound-specific signatures. https://doi.org/10.1289/EHP6233.
Assuntos
Caprilatos/toxicidade , Fluorocarbonos/toxicidade , Hidrocarbonetos Fluorados/toxicidade , Placenta/efeitos dos fármacos , Testes de Toxicidade , Animais , Feminino , Camundongos , Neprilisina , Gravidez/efeitos dos fármacosRESUMO
Exposure to endocrine disrupting chemicals has been suggested to contribute to the ongoing globally increasing obesity trend. The complex chemical mixtures that humans and wildlife are exposed to include a number of compounds that may have obesogenic properties. In this study we examined a mixture consisting of phthalate-monoesters, triclosan, and perfluorinated compounds. The mixture was designed within the EDC-MixRisk project based on serum levels of the compounds in pregnant women of a Swedish mother-child cohort. The compounds were negatively associated with birth weight of the children. We assessed whether developmental exposure to this mixture in combination with a calorie-rich diet affected metabolic rate, blood lipids, adipogenesis and lipid storage, and the whole-body level of neutral lipids in zebrafish (Danio rerio). Wildtype zebrafish were exposed to the mixture from 3â¯h post fertilization to 5, 14 or 17 days post fertilization (dpf) at water concentrations corresponding to 1, 10, 20, or 100 times the geometrical mean of the serum concentration (hsc) in the women. Exposure to the mixture at 20 times hsc lowered metabolic rate at 2-5 dpf, and increased the number of adipocytes and the amount of visceral adipose tissue at 14 and 17 dpf respectively. Also, mRNA expression of fatty acid binding protein 11a was increased at 17 dpf by 10 and 20 times hsc of the mixture. This study shows that a human-relevant mixture of environmental pollutants affects metabolic rate, adipogenesis and lipid storage in young zebrafish fed a calorie-rich diet, thus demonstrating its potential to disrupt metabolism.
Assuntos
Adipogenia/efeitos dos fármacos , Metabolismo Basal/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Animais , Peso ao Nascer/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/biossíntese , Proteínas de Ligação a Ácido Graxo/genética , Feminino , Humanos , Hidrocarbonetos Fluorados/toxicidade , Ácidos Ftálicos/toxicidade , Gravidez , Triclosan/toxicidade , Proteínas de Peixe-Zebra/biossíntese , Proteínas de Peixe-Zebra/genéticaRESUMO
Most pyrethroid insecticides (PYRs) share a similar primary target site in mammals. However, the potency estimates of the lethal and sublethal effects of these compounds differ up to 103-fold. The aim of this study was to evaluate the relationship between the dose administered, the target tissue dose, and the effect of 2 highly toxic PYRs, tefluthrin (TEF; 0.1-9 mg/kg) and bifenthrin (BIF; 0.5-12 mg/kg), by using the oral route, a corn oil vehicle (1 ml/kg) and subcutaneous temperature (Tsc) monitoring assays in adult rats. The Tsc was determined at 30-min intervals for 5 h (TEF) or 4.5 h (BIF) after dosing. Rats were sacrificed at 6 h after dosing, and BIF and TEF concentrations were determined in blood (Bd), liver (Lv), and cerebellum (Cb) by using a GC-ECD system. The minimal effective dose of BIF (3 mg/kg) affecting Tsc was similar to that found in prior studies using other testing paradigms. Regarding TEF, a very steep relationship between the dose administered and toxicity was observed, with a near-threshold to low-effective range for Tsc at 0.1-6 mg/kg, and a near lethal syndrome at ≥ 7.5 mg/kg. At 6-7.5 mg/kg TEF, the Cb/Bd and Cb/Lv concentration ratios were both > 1. Conversely, for BIF, the Cb concentration was barely over the Bd concentration and the Cb/Lv concentration ratio remained < 1. Our results and previous findings call for more comprehensive consideration to establish the relevance of the distribution into target tissues and the tissue dosimetry for health risks through the exposure to PYRs in humans.
Assuntos
Envelhecimento/metabolismo , Cerebelo/efeitos dos fármacos , Ciclopropanos/toxicidade , Hidrocarbonetos Fluorados/toxicidade , Fígado/efeitos dos fármacos , Piretrinas/toxicidade , Administração Oral , Envelhecimento/sangue , Animais , Temperatura Corporal/efeitos dos fármacos , Cerebelo/metabolismo , Ciclopropanos/administração & dosagem , Ciclopropanos/sangue , Relação Dose-Resposta a Droga , Hidrocarbonetos Fluorados/administração & dosagem , Hidrocarbonetos Fluorados/sangue , Fígado/metabolismo , Masculino , Piretrinas/administração & dosagem , Piretrinas/sangue , Ratos , Ratos Wistar , Distribuição Tecidual , ToxicocinéticaRESUMO
In this study, a rapid, sensitive, and selective method was established for the detection of oxathiapiprolin and the metabolite IN-E8S72, as well as its glucose conjugate IN-SXS67 in cucumber using modified QuEChERS procedure combined with HPLC-MS/MS. The LOQs for all compounds were 0.02 mg kg-1, and the average recoveries were 77.4-111.3% with RSDs of 1.0-8.5%. Under the optimized conditions, the established method was successfully used to determine field samples in dissipation and terminal residue studies. The dissipation study results showed that oxathiapiprolin dissipated rapidly in cucumber with half-lives of 2.4-4.0 days. On the basis of the terminal residue results, the risk assessment was conducted, and both the international estimated daily intake (IEDI) or national estimated daily intake (NEDI) of oxathiapiprolin were much less than 100% which indicate a low health risk to consumers. This work provides guidance for establishing MRL of oxathiapiprolin in China and is of great significance for evaluating its dietary risk in cucumber.
Assuntos
Cucumis sativus/química , Fungicidas Industriais/análise , Hidrocarbonetos Fluorados/análise , Resíduos de Praguicidas/análise , Pirazóis/análise , China , Cromatografia Líquida de Alta Pressão , Qualidade de Produtos para o Consumidor , Cucumis sativus/metabolismo , Contaminação de Alimentos/análise , Fungicidas Industriais/metabolismo , Fungicidas Industriais/toxicidade , Humanos , Hidrocarbonetos Fluorados/metabolismo , Hidrocarbonetos Fluorados/toxicidade , Resíduos de Praguicidas/metabolismo , Resíduos de Praguicidas/toxicidade , Pirazóis/metabolismo , Pirazóis/toxicidade , Medição de Risco , Espectrometria de Massas em TandemRESUMO
Fluorinated diiodine alkanes (FDIAs) are environmental pollutants, including octafluoro-1,4-diiodobutane (PFBDI), hexadecafluoro-1,8-diiodooctane (PFODI) and dodecafluoro-1,6-diiodohexane (PFHxDI). They showed an estrogenic effect in in vitro studies. However, little information is currently available regarding the toxicity of FDIAs in in vivo studies. Zebrafish (Danio rerio) is a vertebrate animal model that is increasingly used for toxicity and efficacy screening as well as for assessing the toxicity and safety of novel compounds, pollutants and pharmaceuticals. In the present study, we investigated the developmental toxicity of FDIAs (PFBDI, PFHxDI and PFODI) and the specific endocrine-related gene expression in zebrafish embryos. The results revealed that all three FDIAs showed developmental toxicity on zebrafish embryos. The half-maximal effective concentration values for PFBDI, PFHxDI and PFODI were 0.89 ± 0.07, 0.53 ± 0.04 and 0.04 ± 0.007 mm, respectively. PFHxDI exhibited the highest developmental toxicity compared with the other FDIAs. In addition, all three FDIAs significantly upregulated the expression of estrogen receptor (esr)1 and cytochrome P450 (CYP) 19b (CYP19b), but did not significantly affect the expression of esr2b, CYP17 and CYP19a in zebrafish. The upregulation effect of PFHxDI was greater than the effect of PFBDI and PFODI. This study furthers our knowledge on the effects of FDIAs on the developmental toxicity and the specific endocrine-related gene expression in the embryo-larval stages of zebrafish. Our results provided a preliminary insight into the toxicity of FDIAs in zebrafish, which will be of great relevance regarding future studies on FDIAs in the environment.
Assuntos
Embrião não Mamífero/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Expressão Gênica/efeitos dos fármacos , Hidrocarbonetos Fluorados/toxicidade , Hidrocarbonetos Halogenados/toxicidade , Larva/efeitos dos fármacos , Peixe-Zebra/crescimento & desenvolvimento , Animais , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Embrionário/genética , Disruptores Endócrinos/química , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Halogenados/química , Larva/genética , Larva/crescimento & desenvolvimento , Dose Letal Mediana , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genéticaRESUMO
Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate, also known as GenX, is a processing aid used in the manufacture of fluoropolymers. GenX is one of several chemistries developed as an alternative to long-chain poly-fluoroalkyl substances, which tend to have long clearance half-lives and are environmentally persistent. Unlike poly-fluoroalkyl substances, GenX has more rapid clearance, but has been detected in US and international water sources. There are currently no federal drinking water standards for GenX in the USA; therefore, we developed a non-cancer oral reference dose (RfD) for GenX based on available repeated dose studies. The review of the available data indicate that GenX is unlikely to be genotoxic. A combination of traditional frequentist benchmark dose models and Bayesian benchmark dose models were used derive relevant points of departure from mammalian toxicity studies. In addition, deterministic and probabilistic RfD values were developed using available tools and regulatory guidance. The two approaches resulted in a narrow range of RfD values for liver lesions observed in a 2-year bioassay in rats (0.01-0.02 mg/kg/day). The probabilistic approach resulted in the lower, i.e., more conservative RfD. The probabilistic RfD of 0.01 mg/kg/day results in a maximum contaminant level goal of 70 ppb. It is anticipated that these values, along with the hazard identification and dose-response modeling described herein, should be informative for risk assessors and regulators interested in setting health-protective drinking water guideline values for GenX.